6gb2 › Citations

Unique features of mammalian mitochondrial translation initiation revealed by cryo-EM.

Kummer E, Leibundgut M, Rackham O, Lee RG, Boehringer D, Filipovska A, Ban N
Nature 560 263-267 (2018)
Related entries: 6gaw, 6gaz

Cited: 54 times
EuropePMC logo PMID: 30089917

Abstract

Mitochondria maintain their own specialized protein synthesis machinery, which in mammals is used exclusively for the synthesis of the membrane proteins responsible for oxidative phosphorylation1,2. The initiation of protein synthesis in mitochondria differs substantially from bacterial or cytosolic translation systems. Mitochondrial translation initiation lacks initiation factor 1, which is essential in all other translation systems from bacteria to mammals3,4. Furthermore, only one type of methionyl transfer RNA (tRNAMet) is used for both initiation and elongation4,5, necessitating that the initiation factor specifically recognizes the formylated version of tRNAMet (fMet-tRNAMet). Lastly, most mitochondrial mRNAs do not possess 5' leader sequences to promote mRNA binding to the ribosome2. There is currently little mechanistic insight into mammalian mitochondrial translation initiation, and it is not clear how mRNA engagement, initiator-tRNA recruitment and start-codon selection occur. Here we determine the cryo-EM structure of the complete translation initiation complex from mammalian mitochondria at 3.2 Å. We describe the function of an additional domain insertion that is present in the mammalian mitochondrial initiation factor 2 (mtIF2). By closing the decoding centre, this insertion stabilizes the binding of leaderless mRNAs and induces conformational changes in the rRNA nucleotides involved in decoding. We identify unique features of mtIF2 that are required for specific recognition of fMet-tRNAMet and regulation of its GTPase activity. Finally, we observe that the ribosomal tunnel in the initiating ribosome is blocked by insertion of the N-terminal portion of mitochondrial protein mL45, which becomes exposed as the ribosome switches to elongation mode and may have an additional role in targeting of mitochondrial ribosomes to the protein-conducting pore in the inner mitochondrial membrane.

Reviews citing this publication (14)

  1. Mechanisms and regulation of protein synthesis in mitochondria. Kummer E, Ban N. Nat Rev Mol Cell Biol 22 307-325 (2021)
  2. Transport of Proteins into Mitochondria. Hansen KG, Herrmann JM. Protein J 38 330-342 (2019)
  3. Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease. Wang F, Zhang D, Zhang D, Li P, Gao Y. Front Cell Dev Biol 9 675465 (2021)
  4. Organization and expression of the mammalian mitochondrial genome. Rackham O, Filipovska A. Nat Rev Genet 23 606-623 (2022)
  5. The Diseased Mitoribosome. Ferrari A, Del'Olio S, Barrientos A. FEBS Lett 595 1025-1061 (2021)
  6. Human Mitoribosome Biogenesis and Its Emerging Links to Disease. Lopez Sanchez MIG, Krüger A, Shiriaev DI, Liu Y, Rorbach J. Int J Mol Sci 22 3827 (2021)
  7. Recent Advances in Archaeal Translation Initiation. Schmitt E, Coureux PD, Kazan R, Bourgeois G, Lazennec-Schurdevin C, Mechulam Y. Front Microbiol 11 584152 (2020)
  8. Regulation of translation by one-carbon metabolism in bacteria and eukaryotic organelles. Shetty S, Varshney U. J Biol Chem 296 100088 (2021)
  9. Translation initiation in mammalian mitochondria- a prokaryotic perspective. Ayyub SA, Varshney U. RNA Biol 17 165-175 (2020)
  10. Targeting and Insertion of Membrane Proteins in Mitochondria. Eaglesfield R, Tokatlidis K. Front Cell Dev Biol 9 803205 (2021)
  11. Epitranscriptomics of Mammalian Mitochondrial Ribosomal RNA. Laptev I, Dontsova O, Sergiev P. Cells 9 E2181 (2020)
  12. Is mitochondrial gene expression coordinated or stochastic? Lee RG, Rudler DL, Rackham O, Filipovska A. Biochem Soc Trans 46 1239-1246 (2018)
  13. Maintaining mitochondrial ribosome function: The role of ribosome rescue and recycling factors. Nadler F, Lavdovskaia E, Richter-Dennerlein R. RNA Biol 19 117-131 (2022)
  14. Types and Functions of Mitoribosome-Specific Ribosomal Proteins across Eukaryotes. Scaltsoyiannes V, Corre N, Waltz F, Giegé P. Int J Mol Sci 23 3474 (2022)

Articles citing this publication (40)

  1. Evolutionary shift toward protein-based architecture in trypanosomal mitochondrial ribosomes. Ramrath DJF, Niemann M, Leibundgut M, Bieri P, Prange C, Horn EK, Leitner A, Boehringer D, Schneider A, Ban N. Science 362 eaau7735 (2018)
  2. Mechanism of membrane-tethered mitochondrial protein synthesis. Itoh Y, Andréll J, Choi A, Richter U, Maiti P, Best RB, Barrientos A, Battersby BJ, Amunts A. Science 371 846-849 (2021)
  3. Structural basis of mitochondrial translation. Aibara S, Singh V, Modelska A, Amunts A. Elife 9 e58362 (2020)
  4. Mitochondrial ribosomal protein PTCD3 mutations cause oxidative phosphorylation defects with Leigh syndrome. Borna NN, Kishita Y, Kohda M, Lim SC, Shimura M, Wu Y, Mogushi K, Yatsuka Y, Harashima H, Hisatomi Y, Fushimi T, Ichimoto K, Murayama K, Ohtake A, Okazaki Y. Neurogenetics 20 9-25 (2019)
  5. Distinct pre-initiation steps in human mitochondrial translation. Khawaja A, Itoh Y, Remes C, Spåhr H, Yukhnovets O, Höfig H, Amunts A, Rorbach J. Nat Commun 11 2932 (2020)
  6. Fidelity of translation initiation is required for coordinated respiratory complex assembly. Rudler DL, Hughes LA, Perks KL, Richman TR, Kuznetsova I, Ermer JA, Abudulai LN, Shearwood AJ, Viola HM, Hool LC, Siira SJ, Rackham O, Filipovska A. Sci Adv 5 eaay2118 (2019)
  7. Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis. Wang YP, Sharda A, Xu SN, van Gastel N, Man CH, Choi U, Leong WZ, Li X, Scadden DT. Cell Metab 33 1027-1041.e8 (2021)
  8. Structure of Human Mitochondrial Translation Initiation Factor 3 Bound to the Small Ribosomal Subunit. Koripella RK, Sharma MR, Haque ME, Risteff P, Spremulli LL, Agrawal RK. iScience 12 76-86 (2019)
  9. Structure of the mature kinetoplastids mitoribosome and insights into its large subunit biogenesis. Soufari H, Waltz F, Parrot C, Durrieu-Gaillard S, Bochler A, Kuhn L, Sissler M, Hashem Y. Proc Natl Acad Sci U S A 117 29851-29861 (2020)
  10. Structural insights into mammalian mitochondrial translation elongation catalyzed by mtEFG1. Kummer E, Ban N. EMBO J 39 e104820 (2020)
  11. Structural insights into unique features of the human mitochondrial ribosome recycling. Koripella RK, Sharma MR, Risteff P, Keshavan P, Agrawal RK. Proc Natl Acad Sci U S A 116 8283-8288 (2019)
  12. Structures of the human mitochondrial ribosome bound to EF-G1 reveal distinct features of mitochondrial translation elongation. Koripella RK, Sharma MR, Bhargava K, Datta PP, Kaushal PS, Keshavan P, Spremulli LL, Banavali NK, Agrawal RK. Nat Commun 11 3830 (2020)
  13. Mechanism of mitoribosomal small subunit biogenesis and preinitiation. Itoh Y, Khawaja A, Laptev I, Cipullo M, Atanassov I, Sergiev P, Rorbach J, Amunts A. Nature 606 603-608 (2022)
  14. How to build a ribosome from RNA fragments in Chlamydomonas mitochondria. Waltz F, Salinas-Giegé T, Englmeier R, Meichel H, Soufari H, Kuhn L, Pfeffer S, Förster F, Engel BD, Giegé P, Drouard L, Hashem Y. Nat Commun 12 7176 (2021)
  15. Stepwise maturation of the peptidyl transferase region of human mitoribosomes. Lenarčič T, Jaskolowski M, Leibundgut M, Scaiola A, Schönhut T, Saurer M, Lee RG, Rackham O, Filipovska A, Ban N. Nat Commun 12 3671 (2021)
  16. Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation. Ferreira N, Perks KL, Rossetti G, Rudler DL, Hughes LA, Ermer JA, Scott LH, Kuznetsova I, Richman TR, Narayana VK, Abudulai LN, Shearwood AJ, Cserne Szappanos H, Tull D, Yeoh GC, Hool LC, Filipovska A, Rackham O. EMBO J 38 e102155 (2019)
  17. The mitoribosome-specific protein mS38 is preferentially required for synthesis of cytochrome c oxidase subunits. Mays JN, Camacho-Villasana Y, Garcia-Villegas R, Perez-Martinez X, Barrientos A, Fontanesi F. Nucleic Acids Res 47 5746-5760 (2019)
  18. Reconstitution of mammalian mitochondrial translation system capable of correct initiation and long polypeptide synthesis from leaderless mRNA. Lee M, Matsunaga N, Akabane S, Yasuda I, Ueda T, Takeuchi-Tomita N. Nucleic Acids Res 49 371-382 (2021)
  19. Single-particle mass analysis of intact ribosomes by mass photometry and Orbitrap-based charge detection mass spectrometry. Lai SH, Tamara S, Heck AJR. iScience 24 103211 (2021)
  20. Mitoribosomal small subunit maturation involves formation of initiation-like complexes. Lenarčič T, Niemann M, Ramrath DJF, Calderaro S, Flügel T, Saurer M, Leibundgut M, Boehringer D, Prange C, Horn EK, Schneider A, Ban N. Proc Natl Acad Sci U S A 119 e2114710118 (2022)
  21. Long-range interdomain communications in eIF5B regulate GTP hydrolysis and translation initiation. Huang BY, Fernández IS. Proc Natl Acad Sci U S A 117 1429-1437 (2020)
  22. Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan. Richman TR, Ermer JA, Siira SJ, Kuznetsova I, Brosnan CA, Rossetti G, Baker J, Perks KL, Cserne Szappanos H, Viola HM, Gray N, Larance M, Hool LC, Zuryn S, Rackham O, Filipovska A. Aging Cell 20 e13408 (2021)
  23. Monitoring mammalian mitochondrial translation with MitoRiboSeq. Li SH, Nofal M, Parsons LR, Rabinowitz JD, Gitai Z. Nat Protoc 16 2802-2825 (2021)
  24. Widespread use of unconventional targeting signals in mitochondrial ribosome proteins. Bykov YS, Flohr T, Boos F, Zung N, Herrmann JM, Schuldiner M. EMBO J 41 e109519 (2022)
  25. Distinct mechanisms of the human mitoribosome recycling and antibiotic resistance. Koripella RK, Deep A, Agrawal EK, Keshavan P, Banavali NK, Agrawal RK. Nat Commun 12 3607 (2021)
  26. Translation initiation of leaderless and polycistronic transcripts in mammalian mitochondria. Remes C, Khawaja A, Pearce SF, Dinan AM, Gopalakrishna S, Cipullo M, Kyriakidis V, Zhang J, Dopico XC, Yukhnovets O, Atanassov I, Firth AE, Cooperman B, Rorbach J. Nucleic Acids Res 51 891-907 (2023)
  27. An Unexpectedly Complex Mitoribosome in Andalucia godoyi, a Protist with the Most Bacteria-like Mitochondrial Genome. Valach M, Gonzalez Alcazar JA, Sarrasin M, Lang BF, Gray MW, Burger G. Mol Biol Evol 38 788-804 (2021)
  28. Biological and Evolutionary Significance of Terminal Extensions of Mitochondrial Translation Initiation Factor 3. Derbikova K, Kuzmenko A, Levitskii S, Klimontova M, Chicherin I, Baleva MV, Krasheninnikov IA, Kamenski P. Int J Mol Sci 19 E3861 (2018)
  29. Heterologous Inferential Analysis (HIA) and Other Emerging Concepts: In Understanding Mitochondrial Variation In Pathogenesis: There is no More Low-Hanging Fruit. Vila-Sanjurjo A, Smith PM, Elson JL. Methods Mol Biol 2277 203-245 (2021)
  30. Leigh syndrome is the main clinical characteristic of PTCD3 deficiency. Muñoz-Pujol G, Ortigoza-Escobar JD, Paredes-Fuentes AJ, Jou C, Ugarteburu O, Gort L, Yubero D, García-Cazorla A, O'Callaghan M, Campistol J, Muchart J, Yépez VA, Gusic M, Gagneur J, Prokisch H, Artuch R, Ribes A, Urreizti R, Tort F. Brain Pathol 33 e13134 (2023)
  31. Translation of MT-ATP6 pathogenic variants reveals distinct regulatory consequences from the co-translational quality control of mitochondrial protein synthesis. Ng KY, Richter U, Jackson CB, Seneca S, Battersby BJ. Hum Mol Genet 31 1230-1241 (2022)
  32. Assembly of the Mitochondrial Translation Initiation Complex. Remes C, Nguyen MD, Spahr H, Ng M, Fritsch C, Bhattacharya A, Li H, Cooperman B, Rorbach J. Methods Mol Biol 2661 217-232 (2023)
  33. Cryo-EM for Structure Determination of Mitochondrial Ribosome Samples. Hillen HS. Methods Mol Biol 2661 89-100 (2023)
  34. Evolution: Mitochondrial Ribosomes Across Species. Agrawal RK, Majumdar S. Methods Mol Biol 2661 7-21 (2023)
  35. Mitochondrial Protein SLIRP Affects Biosynthesis of Cytochrome c Oxidase Subunits in HEK293T Cells. Baleva MV, Piunova U, Chicherin I, Vasilev R, Levitskii S, Kamenski P. Int J Mol Sci 25 93 (2023)
  36. Mitochondrial mRNA Processing in the Chlorophyte Alga Pediastrum duplex and Streptophyte Alga Chara vulgaris Reveals an Evolutionary Branch in Mitochondrial mRNA Processing. Proulex GCR, Meade MJ, Manoylov KM, Cahoon AB. Plants (Basel) 10 576 (2021)
  37. Mitoribosome Biogenesis. Conor Moran J, Del'Olio S, Choi A, Zhong H, Barrientos A. Methods Mol Biol 2661 23-51 (2023)
  38. Structural insights into the role of GTPBP10 in the RNA maturation of the mitoribosome. Nguyen TG, Ritter C, Kummer E. Nat Commun 14 7991 (2023)
  39. The P-type pentatricopeptide repeat protein DWEORG1 is a non-previously reported rPPR protein of Arabidopsis mitochondria. Grüttner S, Nguyen TT, Bruhs A, Mireau H, Kempken F. Sci Rep 12 12492 (2022)
  40. Yeast Mitochondrial Translation Initiation Factor 3 Interacts with Pet111p to Promote COX2 mRNA Translation. Chicherin I, Levitskii S, Baleva MV, Krasheninnikov IA, Patrushev MV, Kamenski P. Int J Mol Sci 21 E3414 (2020)


Quick links